2-Pyridone, addition

Allyltrimethylsilanes react with triplet excited 2,3-dicyano-5,6-dimethylpyra-zine to give diazatricyclooctenes (115), possibly via intermediate (114) formed from ring-opening of an initially-formed [2+2]adduct. Intramolecular [2+2]-cycloaddition yields the pentacyclic compound (116) on irradiation of the corresponding tethered enantiopure bis-2,3-dihydro-4-pyridone. Addition of ethylene to the corresponding a,P-unsaturated-y-lactams in acetone yields (117) and (118) as the major photoproducts. ... 

Durkin P, MagroneP, Matthews S, DaUanoceC, Gallagher T (2002) Lactam enolate-pyridone addition synthesis of 4-halocytisines. Synlett 18 2789-2791... 

The 4-hydroxy-THISs react with electron-deficient alkynes to give cycloadducts (3) that spontaneously eliminate sulfur, producing 2-pyridones (3). Bulky 5-substituents lead to a decrease in the addition rate, and elimination of isocyanate with formation of thiophenes becomes favored (3, 12, 13). Benzyne yields an isolable adduct that exclusively extrudes isocyanate on thermolysis, but sulfur on irradiation (Scheme 7)... 

Elfamycins having 4-hydroxy-2-pyridone moieties (1—6,12) readily undergo reversible internal cyclizations by conjugate addition of either oxygen functionahty on the pyridone ring at C-9. These products can be isolated as exemplified by isoefrotomycin (58). 

A thioamide of isonicotinic acid has also shown tuberculostatic activity in the clinic. The additional substitution on the pyridine ring precludes its preparation from simple starting materials. Reaction of ethyl methyl ketone with ethyl oxalate leads to the ester-diketone, 12 (shown as its enol). Condensation of this with cyanoacetamide gives the substituted pyridone, 13, which contains both the ethyl and carboxyl groups in the desired position. The nitrile group is then excised by means of decarboxylative hydrolysis. Treatment of the pyridone (14) with phosphorus oxychloride converts that compound (after exposure to ethanol to take the acid chloride to the ester) to the chloro-pyridine, 15. The halogen is then removed by catalytic reduction (16). The ester at the 4 position is converted to the desired functionality by successive conversion to the amide (17), dehydration to the nitrile (18), and finally addition of hydrogen sulfide. There is thus obtained ethionamide (19)... 

The addition of 2-butenyl(triisopropoxy)titanium was applied in the total synthesis of the pyridone fragment of the antibiotics aurodox and efrotomycin57. 2-Alkenyltitanium(IV) reagents exhibit outstanding simple diastereoselectivity in reactions with methyl ketones52,58 (see Table 2). 

Fewer procedures have been explored recently for the synthesis of simple six-membered heterocycles by microwave-assisted MCRs. Libraries of 3,5,6-trisubstituted 2-pyridones have been prepared by the rapid solution phase three-component condensation of CH-acidic carbonyl compounds 44, NJ -dimethylformamide dimethyl acetal 45 and methylene active nitriles 47 imder microwave irradiation [77]. In this one-pot, two-step process for the synthesis of simple pyridones, initial condensation between 44 and 45 under solvent-free conditions was facilitated in 5 -10 min at either ambient temperature or 100 ° C by microwave irradiation, depending upon the CH-acidic carbonyl compound 44 used, to give enamine intermediate 46 (Scheme 19). Addition of the nitrile 47 and catalytic piperidine, and irradiation at 100 °C for 5 min, gave a library of 2-pyridones 48 in reasonable overall yield and high individual purities. 

More general processes rely on variations of the Guareschi-Thorpe reaction [14] where condensations between 1,3-dicarbonyls and cyanoacetamide yield functionalized monocyclic 2(lff)-pyridones (a and b. Scheme 2) [15, 16]. Unless the carbonyls are sufficiently different in reactivity, the reaction suffers from poor regioselectivity. The use of 3-alkoxy or 3-amino enones instead of 1,3-dicarbonyls has proven to be a versatile and reliable synthetic methodology where the 1,4-addition controls the regioselective outcome (c and d. Scheme 2) [17-19]. 

As indicated, many of the more highly fimctionalized building blocks did not result in 2-pyridones. However, a thorough structure elucidation of by-products and intermediates was used to propose a mechanism for the formation of the 2-pyridone core based on a Michael addition followed by a Dimroth-type rearrangement (Fig. 3). 

Ring-fused 2-pyridone structures where the additional ring is fused over the nitrogen will be covered in this section. Other ring-fused systems can be obtained simply by using suitable cychc starting materials or by conducting intramolecular reactions, examples for the preparation of such systems can be found in the papers discussed in Sect. 2.2 [42,43]. 

A preliminary test for the biodegradability of the 3-phenyl- and 3-carbamoyl-2(lH)pyridones was conducted in a barnyard humus suspension. The analysis by HPLC showed some loss, and the fluorescent compounds seemed to be adsorbed onto the solid. The 3-carbamoyl-2(lH)pyridone (II) also hydrolyzed to 3-carboxylic acid-2(lH)pyridone both in the slurry test and in water solutions that had been left standing 1-2 weeks. In preliminary tests both the 3-phenyl- and the 3-carbamoyl-2(lH)pyridones apparently adsorbed to some extent on silica sand columns. In addition, the solubility of both 1-H compounds was somewhat low, 1.3 x 10 M for II, and 1.0 x 10 M for IV. 

JCS(P1)2779,92JCS(P1)2789], Thermal cyclization of the adducts (129) and (130), formed by addition of 5-aminoimidazoles (96) to dialkyl acety-lenedicarboxylates (Section V,B,5,c), was found to be facile and gave the imidazo[4,5-6]pyridones (153) [92JCS(P1)2779],... 

The addition-elimination adducts (143)-(145) are also useful precursors to imidazo[4,5-b]pyridines. Thus, the malonate derived products (143) on treatment with hot ethanolic HC1 [92JCS(P1)2789] or hot ethanolic triethylamine (78H241) gave the imidazo[4,5-b]pyridones (157). The dinitrile derivatives (144) gave the ortho amino nitriles (158) by treatment with hot methanolic sodium hydroxide solution and the nitrile esters (145)... 

Michael addition of (benzotriazol-l-yl)acetonitrile 557 to a,[)-unsatu rated ketones followed by heterocyclization provides new means for preparation of 2,4,5-trisubstituted pyridines. The reaction is catalyzed by bases. In the presence of secondary amines, a nucleophilic attack of amine on the CN group in adduct 556 initiates the cyclization to tetrahydropyridine 558 that subsequently eliminates water and benzotriazole to give pyridine 559. Analogously, in the presence of NaOH, pyridone 560 forms, via intermediate 561 (Scheme 88) <1997JOC6210>. 

In the second instance, two approaches seem to be worthy of special note. The synthetic utility of elemental phosphorus based on it acting as a radical trap appears to be quite valuable, but additional effort is required to determine the variability of the source of the organic free radicals. (Is there some other, more efficacious, source of organic free radicals that works better with this system than acylated iV-hydroxy-2-pyridones ) The other approach that appears ripe for development is the hydrolysis/elimination with "phosphorates" derived from the oxidative addition of white phosphorus to alkenes. We look forward to the continued development of such facile approaches toward the preparation of fundamental phosphonic acids. 

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